Speaker: Mr. Sing R. Gurung is a Senior Scientist in Drug Substance Development at GSK, where he develops scalable synthetic processes for small-molecule pharmaceuticals. With over 18 years of experience in process chemistry and chemical development, he has led the design and optimization of routes from laboratory discovery through pilot-plant manufacturing, with expertise in process development, crystallization, reaction optimization, and data-driven process understanding. Prior to joining GSK, he spent more than a decade at AMRI (now Curia) supporting pharmaceutical development programs. Sing holds an M.S. in Organic Chemistry from Western Michigan University and has authored multiple peer-reviewed publications in process chemistry and organic synthesis. He is the recipient of the 2025 GSK Cool Chemistry Award (Gill-Lord Award) for his contributions to atroposelective synthesis.
Title of Talk: LiOTf-Mediated Suppression of Kornblum Oxidation Enables Scalable, Chromatography-Free SN2 Synthesis of an MRGPRX2 Antagonist
Abstract: A key transformation in the convergent synthesis of an MRGPRX2 antagonist was an SN2 displacement between a highly functionalized lactamide electrophile and a difluoropiperidine nucleophile bearing a pyridine N-oxide. The discovery route supplied API for early toxicology studies but suffered from several limitations: an unstable, sensitizing leaving group in the SN2 step, reliance on chiral SFC, poor stereoselectivity in the final API, and two column chromatography purifications. These shortcomings compelled the process chemistry team to develop a more robust, scalable route to enable clinical progression.
When sulfonate leaving groups were used, the SN2 reaction showed excellent stereoselectivity but low yields owing to competing Kornblum-type oxidation of the pyridine N-oxide. Inclusion of stoichiometric lithium triflate (LiOTf) significantly improved conversion and isolated yields. NMR studies indicate Li+ coordinates to the pyridine N-oxide, attenuating its nucleophilicity and suppressing the undesired Kornblum pathway.
The optimized, chromatography-free sequence—formation of the HCl salt, basification with ammonia, and reformation of the HCl salt—furnished the desired solid form and removed the need for chiral SFC and multiple chromatographic steps. The revised process was implemented at multikilogram scale, delivering high stereoselectivity, substantially improved overall yield.